The carcinogenesis process begins with DNA damage and culminates in aberrant cell proliferation. Many phenotypic alterations occur in cells during the course of neoplastic development. Gap junctional communication (GJC) is one such phenotypic alteration, being present in non-neoplastic cells and deficient or lost in neoplastic cells. Significant is the fact that transfection of neoplastic cells with specific connexin (cx) cDNA's (cx26, cx43) suppresses many of the neoplastic cellular phenotypes and restores GJC. The mechanism by which many oncogenes, tumor promoters and growth factors interrupt GJC most likely involves cx phosphorylation. We have found that the Platelet Derived Growth Factor receptor (PDGFr) can signal in the presence or absence of its tyrosine protein kinase (TPK) activity to interrupt GJC. This effect is related to tyrosine (tyr) phosphorylation of cx43 and association of cx43 with the p2l ras GTPase activating protein (GAP). Our objectives are to define the pathway by which both the kinase positive (kin +) and kinase negative (kin-) PDGFr's signal to interrupt GJC and determine if a gatable (wild type cx43) vs a non gatable (either always open or always closed; accomplished by site directed mutagenesis) GJ is required to reverse the transformed phenotype. Five aims are proposed: 1) determine the second messenger protein(s) associated with the PDGFr that leads to interruption of GJC using specific tyr PDGFr mutants; 2) determine the signals down stream of the PDGFr/associated protein complex leading to interruption of GJC; 3) determine how PDGFr affects GJ gating by studying PDGFr-mediated post- translational modification of cx43 proteins; 4) determine how the kin- PDGFr signals to interrupt GJC based on results from specific aims 1-3; and 5) determine if a gatable (wild type cx43) vs a non gatable (either always open or always closed; accomplished by site directed mutagenesis) GJ is required to reverse the transformed phenotype.